PROJECT SUMMARY Passively transferred broadly neutralizing antibodies (bnAbs) are being evaluated in clinical trials for HIV-1 treatment and prevention. The results of these studies in macaques and humans suggest that bnAbs have antiviral activity and possibly a ?vaccinal? effect, i.e. induction of HIV-specific cellular immune responses. After several years of infection, approximately 5-15% of HIV-1 infected individuals develop some ability to cross- neutralize a broad range of heterologous viral strains, with only 1% of individuals developing potent bnAbs. It is possible that individuals with chronic HIV-1 infection have elicited precursors of HIV bnAbs, but that these responses have been stunted by viral escape or by affinity maturation away from highly conserved epitopes. If HIV bnAb precursors have indeed been elicited in these individuals as our preliminary data indicates, then such responses could be boosted by delivery of native-like HIV-1 envelope (Env) trimers. Development of therapies that may induce bnAb in vivo would be a valuable advance for both HIV-1 treatment and prevention. We conducted neutralization assays with curated virus panels that are particularly sensitive to VRC01-class precursor antibodies, V2 apex-precursors and PGT 121 precursor antibodies and demonstrated that the baseline frequencies of bnAb precursors was ~20% in a small cohort (N = 25) of chronically HIV 1-infected individuals receiving suppressive ART. We therefore propose to test if bnAbs can be induced by immunization with native- like Env trimer vaccination in chronic, ART-suppressed HIV-1 infection, including in individuals who have initiated the appropriate pathways of B-cell somatic hypermutation through natural infection. Native-like trimers mimic the structure of Env on the surface of the virus largely correctly and display multiple bnAb epitopes in a manner similar to how these epitopes appear on the virion-associated spike, and can induce autologous primary virus (Tier-2) responses in animal models .Accordingly, we will conduct a Phase 1, randomized, placebo controlled, exploratory dose-escalation study evaluating the safety and immunogenicity of a native-like trimer vaccine, VRC- HIVRGP096-00-VP (Trimer 4571), developed and provided to us by the NIH Vaccine Research Center, in HIV- 1 infected individuals on suppressive ART. We will assess vaccine induced changes in autologous and cross clade virus neutralization and trimer-specific antibody response. Additionally, we will perform detailed mechanistic studies to investigate the effect of bnAb precursor presence on bnAb B-cell lineage development, characterize epitope specificities and assess trimer-induced changes in the B cell repertoire. Using multiple, state-of-the-art assays, we will measure the effect of the immunogen on the size of the peripheral blood HIV-1 reservoir and potential sieving effect on the residual plasma viremia and cellular HIV Env RNA. Trimer induced virologic and immunological assessments will provide new insights into the conditions and the benefits of these neutralizing antibody responses toward achieving sustained HIV-1 remission without ART.